GABAergic interneurons perform crucial roles in cerebral cortical development and function, but little is[unreadable] known about the molecular mechanisms that control interneuron fate determination. Most cortical[unreadable] interneurons originate in the medial ganglionic eminence (MGE) of the ventral forebrain, where recent[unreadable] evidence has begun to further define the origins of distinct subgroups of cortical interneurons[unreadable] (Xu...Anderson, 2004). The experiments described below are designed to examine how molecular signals[unreadable] specify interneurons within the MGE. To achieve this goal we will use a combination of in vivo and in vitro[unreadable] gain and loss of function studies focused on four proteins:[unreadable] 1) Sonic Hedgehog (Shh), a morphogen that promotes ventral neural tube development including the MGE,[unreadable] 2) NKX2.1, a transcription factor target of Shh signaling that is required for normal MGE development,[unreadable] 3) LHX6, a transcription factor that is, downstream of Nkx2.1 in the MGE and is expressed in interneurons[unreadable] migrating to the cerebral cortex,[unreadable] 4) ARX1, also expressed in migrating interneurons, and required for normal interneuron development.[unreadable] Since mutations inShh, Nkx2.1 and Arx1 have been linked to developmental forebrain abnormalities in[unreadable] humans, these studies lay the groundwork for identifying the "molecular code" for interneuron specification[unreadable] that will enhance our understanding of and treatment approaches for a variety of neuropathologic conditions.[unreadable] In addition, these studies are highly synergistic with other aims of the PPG including; the molecular control[unreadable] of cortical and subcortical proliferation by cyclin D2 and Shh (Projects 1 and 3), the role of migratory[unreadable] subcortical interneurons in cortical proliferation (Project 3) and the histological, physiological and behavioral[unreadable] effects of altered interneuron output by the MGE (Projects 1 and 4). In sum, the overarching goal of this[unreadable] project is to link clinically relevant alterations in embryonic forebrain development with postnatal histological[unreadable] and functional phenotypes.